COPD is a highly prevalent disorder with rising mordibity and mortality and there are limited therapeutic options to alter disease course. Patients with a predominance of cough and sputum production are felt to be a distinct phenotypic group with greater airway inflammation; however, the factors underlying persistent inflammation in COPD remain unresolved. The parent study of this proposal examines the effect of roflumilast (a potent and specific PDE4 inhibitor) versus placebo on airway inflammation. This ancillary study provides an unparalled opportunity to examine longitudinal changes in airway microbial structure and function, relating these to inflammation, changes in epithelial gene expression and mucin production. The central hypothesis of this proposal is that changes in the indigenous pulmonary microbiome of COPD patients (either a change in overall community structure or through domination/colonization of the pulmonary mucosa by a single species or limited bacterial consortia) causes changes in epithelial cell gene expression, including activation of the EGFR pathway and mucin induction, thereby contributing to airway obstruction and symptoms of chronic bronchitis in COPD patients. This process will be ameliorated by a PDE4 inhibitor. Specifically, we will 1) define the microbial communities from airway samples in COPD patients; 2) identify bacterial determinants of airway epithelial mucin dysregulation in COPD and whether roflumilast exerts its beneficial effects through reduction in airway mucin production; 3) determine the relationship between localized changes in the bacterial microbiome and epithelial gene expression of pattern recognition receptors (PRRs), anti-microbial peptides and host stress-response pathways and; 4) investigate the interrelationship between changes in the bacterial microbiome (longitudinal & via roflumilast) with epithelial mucin regulation, epithelial gene expression, airway inflammation and clinical phenotype, using mathematical models to identify potential interactions. This proposal will leverage a large, industry sponsored investigation with state of the art methodologies to examine complex microbial communities, epithelial mucin production and airway inflammation in a highly characterized group of COPD subjects with chronic bronchitis. The data generated by these novel experiments will provide novel insight into the contribution of changes in the lung microbiota to changes in disease in highly characterized COPD subjects, utilizing high throughput technologies and systems science approaches.